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GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome
S Kang1, J M Graham, A H Olney
1Laboratory of Genetic Disease Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-4472, USA.
Insights
Pallister-Hall syndrome (PHS) is a genetic disorder linked to the GLI3 gene. Frameshift mutations in GLI3 cause PHS, affecting multiple organ systems in development.
Area of Science:
- Genetics
- Developmental Biology
- Human Pathologies
Background:
- Pallister-Hall syndrome (PHS) is a rare, autosomal dominant disorder characterized by hypothalamic hamartoma, central polydactyly, and other congenital malformations.
- The PHS locus has been mapped to chromosome 7p13, which co-localizes with the GLI3 gene, a key transcription factor in vertebrate development.
- Greig cephalopolysyndactyly syndrome (GCPS) shares some features with PHS, including polysyndactyly and abnormal craniofacial features, and is also linked to GLI3 gene alterations.
Purpose of the Study:
- To investigate the role of the GLI3 gene in the etiology of Pallister-Hall syndrome.
- To identify specific mutations in GLI3 associated with PHS in affected families.
Main Methods:
- Genetic analysis of two families with a clinical diagnosis of Pallister-Hall syndrome.
- Sequencing of the GLI3 gene to identify mutations.
- Analysis of mutation location relative to zinc finger-encoding domains.
Main Results:
- Two distinct frameshift mutations in the GLI3 gene were identified in the two PHS families.
- These mutations were located 3' to the zinc finger-encoding domains of GLI3.
- One of the identified mutations occurred de novo in an affected individual.
Conclusions:
- Autosomal dominant Pallister-Hall syndrome is caused by mutations in the GLI3 gene.
- Frameshift mutations in the GLI3 transcription factor can lead to pleiotropic effects, impacting multiple organ system development.
- These findings expand the spectrum of GLI3-associated disorders and highlight its critical role in vertebrate development.
Abstract:
Pallister-Hall syndrome (PHS, M146510) was first described in 1980 in six newborns. It is a pleiotropic disorder of human development that comprises hypothalamic hamartoma, central polydactyly, and other malformations. This disorder is inherited as an autosomal dominant trait and has been mapped to 7p13 (S. Kang et al. Autosomal dominant Pallister-Hall syndrome maps to 7p13. Am. J. Hum. Genet. 59, A81 (1996)), co-localizing the PHS locus and the GLI3 zinc finger transcription factor gene. Large deletions or translocations resulting in haploinsufficiency of the GLI3 gene have been associated with Greig cephalopolysyndactyly syndrome (GCPS; M175700) although no mutations have been identified in GCPS patients with normal karyotypes. Both PHS and GCPS have polysyndactyly, abnormal craniofacial features and are inherited in an autosomal dominant pattern, but they are clinically distinct. The polydactyly of GCPS is commonly preaxial and that of PHS is typically central or postaxial. No reported cases of GCPS have hypothalamic hamartoma and PHS does not cause hypertelorism or broadening of the nasal root or forehead. The co-localization of the loci for PHS and GCPS led us to investigate GLI3 as a candidate gene for PHS. Herein we report two PHS families with frameshift mutations in GLI3 that are 3' of the zinc finger-encoding domains, including one family with a de novo mutation. These data implicate mutations in GLI3 as the cause of autosomal dominant PHS, and suggest that frameshift mutations of the GLI3 transcription factor gene can alter the development of multiple organ systems in vertebrates.